1. Treatment strategies for the infertile PCO patient Shahar Kol

2. PCOS revised diagnostic criteria ~ 2003 Rotterdam consensus ~ 2 out of 3 criteria required Oligo- and/or anovulation Hyperandrogenism (clinical and/or biochemical) Polycystic ovaries Exclusion of other etiologies 2

3. Multiple Choice Lifestyle modification: Weight loss Clomiphene citrate (CC) Aromatase inhibitors (AI’s) Insulin lowering medications Low dose FSH Laparoscopic ovarian drilling IVF: new options 3

4. Lifestyle modification 4

5. OBESE PCOS - LOSS OF WEIGHT Loss of >5% of body weight -  Reduces - insulin levels - ovarian androgen production - circulating free testosterone Induces ovulation Facilitates ovulation induction Reduces miscarriage rates Kiddy et al,1992;Hamilton-Fairley et al,1992 Kiddy et al,1992;Hamilton-Fairley et al,1992 5

6. Lifestyle modification Behavioural counselling Diet (caloric restriction) & exercise Bariatric surgery 6

7. Lifestyle changes in women with polycystic ovary syndrome 2011 There was no evidence of effect for lifestyle intervention on improving glucose tolerance or lipid profiles and no literature assessing clinical reproductive outcomes. Long term complicated studies, dropout rates, fertility seeking patients are impatient… 7

8. Clomiphene Citrate Treatment ER ER E2 FSH Day 5 CCER ER 8

9. Clomiphene Citrate 9

10. Response to clomiphene No response 27% Ovulation & pregnancy Ovulation -No pregnancy 37% 36% 10

11. Should we monitor clomiphene cycles with ultrasound? No U/S or hCGWith U/S + hCG 150105n 34.7%48% Cumulative pregnancy rate 26.7%35.6%Deliveries 10 Multiple pregnancies 11

12. Non-Response to Clomiphene Failure to ovulate Androgens BMI LH Insulin 12

13. Reasons for Clomiphene Failure Ovulation but no conception Anti-estrogen effects - cervical mucus - endometrium Fetal toxicity: category X 13

14. Anti-estrogen effect on endometrium 14

15. AI’s Original Article Letrozole versus Clomiphene for Infertility in the Polycystic Ovary Syndrome Richard S. Legro, M.D., Robert G. Brzyski, M.D., Ph.D., Michael P. Diamond, M.D., Christos Coutifaris, M.D., Ph.D., William D. Schlaff, M.D., Peter Casson, M.D., Gregory M. Christman, M.D., Hao Huang, M.D., M.P.H., Qingshang Yan, Ph.D., Ruben Alvero, M.D., Daniel J. Haisenleder, Ph.D., Kurt T. Barnhart, M.D., G. Wright Bates, M.D., Rebecca Usadi, M.D., Scott Lucidi, M.D., Valerie Baker, M.D., J.C. Trussell, M.D., Stephen A. Krawetz, Ph.D., Peter Snyder, M.D., Dana Ohl, M.D., Nanette Santoro, M.D., Esther Eisenberg, M.D., M.P.H., Heping Zhang, Ph.D., for the NICHD Reproductive Medicine Network N Engl J Med Volume 371(2):119-129 July 10, 2014 15

16. Study Overview This double-blind, multicenter, randomized trial showed that letrozole, as compared with clomiphene, was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. 16

17. Kaplan–Meier Curves for Live Birth. Legro RS et al. N Engl J Med 2014;371:119-129 17

18. Outcomes with Regard to Live Birth, Ovulation, Pregnancy, Pregnancy Loss, and Fecundity. 18

19. All Serious Adverse Events, plus Other Adverse Events with Significant Differences between the Treatment Groups. 19

20. Congenital malformations Letrozole: imperforate anus + spina bifida, Dandy walker, CP, VSD CC: VSD+pul stenosis 20

21. In 2005, some concern was raised as a result of an abstract (Biljan et al) of a study that compared 150 babies born to women who had used letrozole with 36,005 babies born to low-risk pregnant women. The results of this study, which had several methodological issues, suggested that letrozole might increase the risk of cardiac and bone anomalies; however, the overall rate of major malformations did not differ between the 2 groups. Following the publication of this abstract, the manufacturer of letrozole (Novartis) issued a statement to physicians contraindicating the use of letrozole in pre- menopausal women. 21

22. COCHRANE September 2014 Letrozole appears to improve live birth and pregnancy rates in subfertile women with anovulatory PCOS, compared to clomiphene citrate. Due to the short halflife elimination time of letrozole it should be completely cleared out of the system before implantation takes place. OHSS was a very rare event, with no occurrences in most studies. 22

23. Letrozole vs. CC Treatment timing is the same, but… Letrozole: Half life: 2 days. Pregnancy category D CC: Half life: 5-7 days. Pregnancy category X CC is used routinely for 60+ years…Letrozole is off-label? 23

24. GONADOTROPHIN STIMULATION Complications Multiple folliculogenesis Multiple folliculogenesis - OHSS - OHSS - Multiple pregnancies - Multiple pregnancies High miscarriage rate High miscarriage rate 24

25. CONVENTIONAL REGIMEN (IU) 555 Days 5 75 150 225 300 25

26. Results of conventional therapy 14 series, 1966-1984, WHO I & II Hamilton-Fairley & Franks, 1990 26

27. Low-Dose rFSH (“low-slow”) 75-112.5 IU 50-75 IU 100-150 IU 1477 Days 27

28. Low Dose Gonadotropins Summary of Results Patients = 841, Cycles= 1556 Updated from Homburg & Howles, 1999 28

29. Summary – low-dose FSH Only a low-dose protocol should be used for ovulation induction in PCOS. Step-up more efficient and safer than step-down. Small starting and incremental dose increases recommended with no dose change for 14 days. 29

30. Metformin for ovulation induction? 30

31. Screening for insulin resistance in PCOS Should we make a formal assessment of insulin resistance in all women with PCOS? NO 31

32. Live birth rates CC Metformin CC+metformin 22.5% 7.2% 26.8% Legro et al, NEJM, 2007 15.4% 7.9% 21.1% Zain et al, Fertil Steril, 2009 32

33. Metformin alone Obese PCOS 33

34. Insulin-sensitising drugs for women with PCOS, oligo/amenorrhea and subfertility Tang et al. Cochrane Database, 2012 The use of medications to lower insulin levels, such as metformin alone or in combination with drugs to induce ovulation (for example clomiphene citrate), does not increase the chance of having a live birth. Metformin was also associated with increased gastrointestinal symptoms such as nausea and diarrhea. 34

35. LOD for PCOS 35

36. 111 patients, CC resistant CPR: 54% after 12 months 75% after 30 months Diathermy > Argon laser Best if < 3 years infertility, thin and high LH Li et al Br J Obstet Gynaecol 1998; 105: 338 36

37. Laparoscopic 'drilling' by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome, 2012. Ovarian drilling with/out ovulation induction, was as effective as medical ovulation induction alone in inducing ovulation, but the risk of multiple pregnancies was lower in the group of women who had laparoscopic ovarian drilling. Approximately 37% of women will have a live birth and 7% will have a miscarriage with either procedure. 37

38. 2012 Main concern: OHSS Keep the option of agonist trigger Individual patient-based decision: Freeze all? Fresh transfer? If fresh transfer: how to handle luteal phase? IVF 38

39. OHSS PREVENTION: WHAT REALLY WORKS? GnRH agonist versus hCG for oocyte triggering in GnRH antagonist ART cycles Total events 0 (GnRH) 21 (hCG) 39

40. A safe and OHSS-free clinical environment 40

41. Engmann et al, 2008 LUTEAL PHASE: INTENSIVE E+P OHSS high-risk patients 41

42. 42

43. HCG-BASED LUTEAL SUPPORT: FIXED TIME POINTS 1,000 IU with trigger (Griffin) 1,500 IU with OPU (Humaidan) 1,500 IU 3 days post OPU (Haas) Can we be more patient specific??? Can we tailor hCG support to a specific patient endocrine response??? 43

44. COASTING A popular OHSS prevention strategy. So far, follicular phase only. In OHSS high risk situation: stop gonadotropin. Follow E2 level daily. Individualized approach. Trigger with hCG when E2 drops below a cutoff level. Mechanism: partial follicular demise. 44

45. CASE #1 30 year old, mechanical + male factors, AFC=15 Short antagonist protocol, starting dose Menopur 112.5 daily, last 3 days 75. On trigger (0.2 mg triptorelin) day E2=19017 pmol/l, P=2.5 nmol/l, LH=2.1 IU, >20 follicles >11 mm OPU=20 oocytes, 12 injected, 4 normal fertilization, 2 embryos transferred on day 2, 2 frozen. 45

46. CASE #1, P POST AGONIST TRIGGER hCG 1,500 IU ET BETA=316 46

47. OUTCOME Moderate OHSS Ongoing singleton pregnancy 47

48. A 27 year old patient, severe OTA syndrome. A previous IVF cycle 7 years ago resulted in live birth. Three IVF trials failed during the last 4 years. Stimulation: antagonist-based, 150 IU Menopur. A day before trigger E2=15768 P=3.2 LH=1.2, with >30 follicles >11 mm. Trigger with triptorelin 0.2 mg 25 oocytes were retrieved, 23 injected with sperm, 11 normal 2pn fertilizations. 2 embryos transferred 48 hours post retrieval, 8 were frozen. CASE #2 48

49. CASE #2, P POST AGONIST TRIGGER hCG 1,500 IU ET BETA=174 49

50. No OHSS Ongoing twin pregnancy OUTCOME 50

51. THE QUESTION OF IMPLANTATION POTENTIAL POST EXCESSIVE OVARIAN RESPONSE Clinical evidence for a detrimental effect on uterine receptivity of high serum oestradiol concentrations in high and normal responder patients. Simon et al, 1995 Lower implantation rates in high responders: evidence for an altered endocrine milieu during the preimplantation period. Pellicer et al, 1996 Is it secondary to insufficient P during implantation window? 51

52. CONCLUSION Luteal coasting in high responders is a viable option if fresh transfer is desirable. Cutoff P levels yet to be determined. LH activity –dependent luteal support does not require additional E2 and/or P : patient comfort. Despite extreme E2 levels, good clinical outcome is possible if endogenous P secretion is high enough during implantation window. 52

53. PUTTING IT ALL TOGETHER FOR THE PCOS IVF PATIENT Always choose antagonist protocol so agonist trigger can be used. Mild stimulation is the aim. Assess risk: age, BMI, previous history, number of follicles>12 mm, estradiol level. If in doubt – freeze all. If low risk: agonist trigger followed by hCG 1500 IU on retrieval day, progesterone to follow. Consider luteal coasting 53

54. Thank You 54